Each year approximately three quarters of a million Americans will have a new myocardial infarction (MI), and approximately half a million will have a recurrent MI. Approximately 37% of these patients will die from the MI within one year, and of those who do survive, two-thirds do not make a complete recovery, leading to an extremely large patient population that progresses to heart failure. No current therapies exist that directly address the negative left ventricular (LV) remodeling process that occurs post-MI and results in heart failure. These staggering statistics necessitate the development of new innovative therapies for MI. This research program will establish a new paradigm in the design of treatments for healing heart tissue post-MI. Specifically our plan is to develop self-assembling materials programmed to form a healing scaffold in damaged heart tissue immediately following MI. Currently, such early treatment is not possible because it would require direct injection of materials into inflamed tissue constituting an unacceptable risk. In the proposed, unprecedented approach, the materials are designed to be injected intravenously rather than directly into heart tissue. They will circulate, and assemble into the healing scaffold in response to inflammatory enzymes present in damaged heart tissue (matrix metalloproteinases, MMPs). We hypothesize that, if such a material could be delivered to a patient's heart within the first day post-MI, this could prevent significant damage by immediately stabilizing the extracellular matrix framework, and then promoting cell infiltration to alter the typical infarct process. The proposed research program will develop novel nanoparticles capable of forming a scaffold material architecture in response to MMPs in damaged heart tissue. This process of enzyme-directed assembly has been proven in vitro in preliminary studies. We aim to optimize and test these nanoparticles in established in vivo animal models. Our overarching aim is therefore to develop autonomously assembling nanomaterial scaffolds, which can be delivered via IV injection, target the area of acute MI, prevent and/or slow negative left ventricular remodeling, and improve cardiac function post-MI.